X-134425256-C-T

Variant names:

• chrX-134425256-C-T
• rs132630297
• NM_001015877.2:c.1024C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001015877.2(PHF6):​c.1024C>T​(p.Arg342*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHF6 NM_001015877.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.55
• Publications: 23 publications found

Genes affected

PHF6 (HGNC:18145): (PHD finger protein 6) This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus. Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Borjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate splicing results in multiple transcript variants, encoding different isoforms. [provided by RefSeq, Jun 2010]

PHF6 Gene-Disease associations (from GenCC):

• Borjeson-Forssman-Lehmann syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-134425256-C-T is Pathogenic according to our data. Variant chrX-134425256-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015877.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	NM_001015877.2	MANE Select	c.1024C>T	p.Arg342*	stop_gained	Exon 10 of 11	NP_001015877.1
	PHF6	NM_032458.3		c.1024C>T	p.Arg342*	stop_gained	Exon 10 of 10	NP_115834.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	ENST00000370803.8	TSL:1 MANE Select	c.1024C>T	p.Arg342*	stop_gained	Exon 10 of 11	ENSP00000359839.4
	PHF6	ENST00000332070.7	TSL:1	c.1024C>T	p.Arg342*	stop_gained	Exon 10 of 10	ENSP00000329097.3
	PHF6	ENST00000625464.2	TSL:5	c.1027C>T	p.Arg343*	stop_gained	Exon 10 of 11	ENSP00000487420.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:4

Jun 09, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 17, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg342*) in the PHF6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the PHF6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Borjeson–Forssman–Lehmann Syndrome (PMID: 12415272, 15241480, 28554332, Invitae). ClinVar contains an entry for this variant (Variation ID: 11063). For these reasons, this variant has been classified as Pathogenic.

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHF6: PVS1, PM2

Sep 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 24 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies of mouse models suggest reduced transcription, impaired regulation, and loss of protein expression compared to wildtype (PMID: 33772537, 38429579); This variant is associated with the following publications: (PMID: 28554332, 33057194, 35904121, 15241480, 33504798, 35982159, 31785789, 35662002, 38787418, 33149206, 37704779, 38429579, 12415272, 33772537)

Intellectual disability Pathogenic:1

Oct 03, 2024

Human Genetics Laboratory, State University of Rio de Janeiro

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The pathogenic variant in the PHF6 gene (NM_001015877.2:c.1024C>T; p.Arg342*, rs132630297) is a recurrent mutation initially identified in the original Börjeson-Forssman-Lehmann Syndrome family. This variant introduces a premature stop codon, potentially leading to transcript degradation via nonsense-mediated decay. According to the ACMG guidelines, the variant is pathogenic (criteria PVS1, PM2, PP5). PVS1 - pathogenic Moderate, null variant in a gene where the loss of function is a known mechanism of disease; PM2 - pathogenic Moderate, extremely low frequency in gnomAD population databases; PP5 - pathogenic Very Strong, reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.5
Vest4		0.71
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs132630297; hg19: chrX-133559286; COSMIC: COSV59699091;